1. Field of the Invention
The present invention relates to a novel method for treatment or prophylaxis of Parkinson's disease. The present invention also relates to a novel agent for treatment or prophylaxis of Parkinson's disease. Further, the present invention relates to a novel method for enhancing dopamine signals in the brain.
2. Prior Art
Parkinson's disease (also referred to as PD) is a progressive degenerate disorder of the central nervous system, characterized by symptoms such as tremor, rigidity, akinesia, postural reflex abnormalities (postural disturbance), etc.
With a partial exception of juvenile Parkinsonism, development of PD is frequently seen in 40's or 50's or later, and it is a disease of a high incidence, affecting one out of 2000 people (in the age of 65 or older, one out of 500 people).
Although neurons in the brain are lost and degenerated with aging even in a normal case, in a patient of the Parkinson's disease, significant loss and degeneration of neurons are observed in the substantia nigra of the midbrain, beyond a rate of normal aging. Therefore, it is thought that various kinds of symptoms of Parkinson's disease are caused due to decreasing of dopamine, which is one of the neurotransmitters produced in the substantia nigra of the midbrain.
Dopamine is involved in regulation of postural maintenance and speed of movement, and when an amount of dopamine produced is decreased, the symptoms of Parkinson's disease develops. It is known that dopamine decrease and development of symptoms have a close relationship. Further, when dopamine is decreased, a balance is lost between dopamine and acetylcholine, which is another neurotransmitter, leading to the symptoms of Parkinson's disease.
As stated above, Parkinson's disease is a representative disorder of the central nervous system, whose symptoms is expected to be alleviated by enhancement of dopamine signals in the brain, and as a therapeutic agent therefore, L-dopa, a dopamine precursor, etc. is employed.
Parkinson's disease and a treatment method thereof are summarized in review by Marsden et al. and Calne et al. (Marsden, Lancet, 1990, pp. 948-952; Calne, New England Journal of Medicine, 1993, vol. 329, pp. 1021-1027).
Among the therapeutic agents for Parkinson's disease, L-dopa is the most frequently used therapeutic agent. L-dopa is a precursor of dopamine, and L-dopa therapy is aimed to supplement dopamine, which is decreased in the substantia nigra-corpus striatum. Since dopamine does not cross the blood brain barrier (BBB), it will not reach the brain if it is administered into a circulating blood. However, L-dopa does cross the blood brain barrier (BBB), and it is metabolized by dopa decarboxylase in the brain to give dopamine, which in turn acts on a dopaminergic receptor.
However, along-termed administration of L-dopa causes complications such as dyskinesia, etc. Further, it has a problem of instability such as wearing-off phenomenon, on-off phenomenon, etc., or problem of showing unexpected reaction or involuntary movements.
Under such circumstances, there have been needs for developing a new excellent therapeutic agent for Parkinson's disease, or a new concomitant agent to avoid a high-dose administration of L-dopa.
Meanwhile, the following facts have been known, regarding a cyclic nucleotide phosphodiesterase of mammals. The cyclic nucleotide phosphodiesterase (hereinafter simply abbreviated as phosphodiesterase or PDE) is an enzyme that hydrolyzes a phosphodiester bond in a cyclic nucleotide such as cAMP (adenosine 3′,5′-cyclic monophosphate) or cGMP (guanosine 3′,5′-cyclic monophosphate), etc. as a substrate, to generate nucleotides such as 5′AMP (adenosine 5′-monophosphate) or 5′GMP (guanosine 5′-monophosphate), etc.
Cyclic nucleotides such as cAMP, cGMP, etc. are involved in regulations of many in vivo functions as the second messenger in the intracellular signal transduction. Intracellular concentrations of the cAMP and cGMP, changing in response to an extracellular signal, are regulated by a balance between an enzyme involved in a synthesis of cAMP and cGMP (adenylate cyclase and guanylate cyclase), and phosphodiesterase (PDE) involved in a hydrolysis thereof.
Until recently, many kinds of the phosphodiesterases have been isolated and identified in mammals, and they have been classified into plural types, according to homology of amino acid sequence, biochemical properties, characterization by an inhibitor, etc. (Beavo, Physiol. Rev., Vol. 75, pp. 725-748, 1995).
For example, PDE1 is Ca2+/calmodulin dependent PDE and hydrolyses both cAMP and cGMP. PDE2 is activated by cGMP and hydrolyses both cAMP and cGMP. PDE classified as PDE3 is inhibited by cGMP. PDE4 specifically recognizes cAMP as a substrate, and is rolipram-sensitive. PDE5 specifically recognizes cGMP as a substrate. PDE6 is a photoreceptor cGMP-PDE. PDE7 specifically recognizes cAMP as a substrate, and is not sensitive to rolipram.
Further recently, existences of 4 kinds of novel types of PDE have been reported. PDE8 specifically recognizes cAMP as a substrate, and PDE9 specifically recognizes cGMP as a substrate. Both of PDE8 and PDE9 are reported to be insensitive to IBMX (3-isobutyl-1-methylxanthine), which is known to be a non-selective PDE inhibitor. Further, PDE11 recognizes both cAMP and cGMP as a substrate.
Regarding PDE10, the followings have been known. Although PDE10 (PDE100A) recognizes both cAMP and cGMP as a substrate, it has been reported to have a stronger affinity for cAMP. Further, cDNAs of human, mouse and rat PDE10A have been isolated and identified. Still further, existence of the PDE10 protein has been confirmed in rat (Fujishige et al., J. Biol. Chem., Vol. 274, pp. 18438-18445, 1999; Kotera et al., Biochem. Biophys. Res. Commun., Vol. 261, pp. 551-557, 1999; Soderling, et al., Proc. Natl. Acad. Sci. USA, vol. 96, pp. 7071-7076, 1999; Loughley, et al., Gene, vol. 234, pp. 109-117, 1999)
As a PDE10 inhibitor, the followings have been known. WO02/48144 (Bayer) discloses a pyrrolo[2,1-a]dihydro-isoquinoline compound having a PDE10 inhibitory activity. It is also described that these compounds with the PDE10 inhibitory activity show antiproliferative activity, and can be used as an anticancer agent. Further, it is also described they can be used for treatment of pains and/or for alleviating a fever in a state of having a fever. Further, in WO01/24781 (NovaNeuron), application of a modulator of PDE10 (PDE10A) for Huntington's disease is disclosed.
The followings have been known regarding a relationship between Parkinson's disease and the phosphodiesterase inhibitors. U.S. Pat. No. 4,147,789 (Sandoz) and U.S. Pat. No. 3,961,060 (Astra Lakemedal) disclose an application of non-specific PDE inhibitors such as caffeine, theophylline, etc., for treatment of Parkinson's disease, together with dopaminergic stimulants.
WO01/78711 (ICOS) discloses an application of a compound having an inhibitory activity on a cGMP specific PDE (PDE5) for treatment of Parkinson's disease.
WO01/32170 (Swope) discloses an application of PDE inhibitor such as sildenafil for a neurological symptom including Parkinson's disease, etc.
Hussain et al. discloses an application of sildenafil, which is PDE5 inhibitor and a medicament for erectile dysfunction for sexual dysfunction of patients of Parkinson's disease (Hussain et al., Journal of Neurology, Nuerosurgery and Psychiatry, 2001, vol. 71, pp. 371-374).
Swope et al. discloses an application of sildenafil for treatment of dyskinesia in Parkinson's disease (Swope, et al., Neurology, 2000, vol. 54, No. 7, pp. A90-A91).
In Dicki et al. and Hulley et al., it is described that a PDE4 inhibitor (Ro20-1724, etc.) is thought to show a protective activity on cells against neurotoxins (MPP+, MPTP, etc.) (Dicki et al., Brain Research, 1997, vol. 753, pp. 335-339; and Hulley et al., Eur. J. Neuroscience, 1995, vol. 7, pp. 2431-2440).
In Kakkar et al., it is described that deprenyl (MAO-B inhibitor) and amantadine, known therapeutic agents for Parkinson's disease are thought to show an inhibitory activity against a calmodulin dependent PDE (PDE1) (Kakkar et al., Brain Research, 1997, vol. 749, pp. 290-294; and Kakkar et al., Life Sciences, 1996, vol. 59, PL337-341).
Fredholm et al. describes that the activity of L-dopa is enhanced by application of PDE inhibitors (caffeine, IBMX, theophyllamine, dipyridamole, etc.) to an animal model (Fredholm et al., European Journal of pharmacology, 1976, vol. 38, pp. 31-38).
Waldeck reports that caffeine affects an activity of dopamine, and also suggests that this may be based on a PDE inhibitory activity that caffeine has (Waldeck, Acta Pharmacol. Toxicol. Suppl., 1975, vol. 36, pp. 1-23).
However, it has not been known, until today, to apply PDE10 inhibitor for treatment of Parkinson's disease.
Further, as regards to a dopaminergic receptor, the following facts have been known. It has been known that several kinds of dopaminergic receptors exist, and that dopamine type 1 receptor (D1-R) and dopamine type 2 receptor (D2-R) are mainly expressed in the brain.
It has been clearly known that Dopamine type 1 receptor (D1-R) conjugates with Gs (Gsα) of G protein and conjugates promotingly with an adenylate cyclase activity. On the other hand, although dopamine type 2 receptor (D2-R) is said to inhibitingly conjugate with adenylate cyclase, there is another theory, and certain points are remained unclear.
An object of the present invention is to provide a novel method for treatment or prophylaxis of Parkinson's disease. Another object is to provide a novel pharmaceutical composition for treatment or prophylaxis of Parkinson's disease. Still further object of the present invention is to provide a novel method or agent for enhancing dopamine signals in the brain in vivo. Objects other than those above are clear from the following descriptions.